ABSTRACT: The cycle-specific schedule-dependent antimetabolite 5-fluorouracil (5-FU) has been in clinical use for 40 years and has evolved as an important agent in the treatment of a large spectrum of tumors, including all gastrointestinal cancers, breast cancer, head and neck cancer, and bladder cancer. Over these 4 decades, there has been an increased understanding of the optimal method and schedule of administration of 5-FU. Furthermore, the concept of pharmacomodulation and biochemical modulation of 5-FU to increase therapeutic efficacy has emerged as a new strategy in cancer chemotherapy. The specific mechanism by which 5-FU induces lethal injury may vary depending on the administration schedule or the type of biochemical modulation applied. The optimal infusion duration and dose intensity of 5-FU continues to be debated as does the question of the need for biochemical modulation when using infusional schedules. Infusional administration of 5-FU has become the gold standard in the treatment of head and neck cancer, esophageal cancer, gastric cancer (in Great Britain), and rectal and anal cancer. The recent availability of oral formulations for 5-FU in conjunction with the capability of manipulating the metabolism of 5-FU, particularly with dihydropyrimidine dehydrogenase (DPD) inhibitors, may provide a substantial incremental improvement in these therapies by eliminating the need for parenteral administration and the use of ambulatory infusion pumps. [ONCOLOGY 12(Suppl 7):19-22, 1998]

Introduction

In 1957, Heidelberger reported on experimental
studies with a new class of tumor inhibitory compounds, the
fluorinated pyrimidines.[1] Because uracil may be preferentially used
in DNA biosynthesis in tumor cells compared with normal cells, it was
conjectured that a fluorine-substituted pyrimidine may be tumor
specific in its inhibitory effect. Early clinical trials reported by
Ansfield confirmed the importance of constant exposure to
5-fluorouracil (5-FU) to achieve a therapeutic effect,[2] and
comparison of slow-infusion 5-FU with bolus administration resulted
in an increased dose with the continuous-infusion schedule.[3]
Despite this evidence, the standard 5-FU administration schedule in
the 1960s and 1970s was a weekly bolus or a 5-day bolus administered
at 4- or 5-week intervals.

The first reports of continuous infusional administration of 5-FU
came from Wayne State University where it was observed that 5-day
infusional 5-FU concomitant with radiation (and mitomycin-C) produced
dramatic responses in some patients with anal cancer.[4] This
observation was followed by a prospective randomized trial reported
in 1975 by Seifert et al comparing daily × 5 bolus dosing with
5-day infusion of 5-FU in advanced colon cancer.[5] In this seminal
study, response rates were doubled on the infusion schedule, though
there was no effect on median survival. Methodologic problems with
the study, however, included imbalances between the two treatment
arms. Furthermore, at that time, the 5-day infusion required
hospitalization, which greatly increased the cost and inconvenience
of treatment compared with outpatient bolus delivery.

The modern era of infusional administration of 5-fluorouracil began
in the early 1980s, and was aided by the availability of central
venous access devices and of ambulatory infusion pumps for outpatient
administration. The rationale for continuous infusion of 5-FU has
always been compelling and is based on its very short half-life of 10
minutes with bolus delivery; and, as an S-phase-specific drug, 5-FU
is predominantly effective in cycling cells, which represent only a
small proportion of the tumor cell mass at any point in time.[6]
Schedule dependency was elegantly demonstrated in the in vitro
experiments by Drewinko.[7] In 1981, Lokich et al began to develop
the concept of protracted infusional 5-FU to maximize the duration of
tumor cell exposure, ultimately to achieve maximal tumor cell
killing. From a series of phase I and phase II trials, several
clinical effects of protracted infusional schedules became
evident[8]: (1) the optimal dose rate and maximum tolerated dose
(MTD) for protracted infusion of ³ 10
weeks was 300 mg/m²/day, (2) increasing the dose rate by as
little as 15% per day resulted in a substantial reduction in the
duration of infusion to £ 3 weeks,
(3) dose-limiting toxicity is stomatitis (diarrhea and hematologic
effects are not observed), and (4) hand-foot syndrome occurs in 25%
to 30% of patients.[9] These studies also demonstrated that
protracted infusion of 5-FU increased the dose intensity (as measured
in mg/m²/wk) by a factor of five compared with bolus
administration, with a very low incidence of toxicity.

In the early phase II studies by Lokich, response rates of 38% were
observed in both previously treated and untreated patients with
advanced colon cancer. Response rates in other studies ranged from
30% to 50%.[10,11]

Phase III Comparative Trials with Infusional vs
Bolus 5-FU

In addition to the original Seifert trial reported in 1975,[5] four
prospective randomized trials have compared infusional 5-FU with
bolus 5-FU (Table 1),[12-15]
results of which have been summarized by Lokich and Anderson.[16,17]
In 1989, Lokich et al reported on the first of three trials in which
infusional 5-FU was evaluated by the Mid-Atlantic Oncology Program
(MAOP). In this prospective randomized trial, protracted infusional
5-FU for 10 weeks was compared with a daily ´ 5 regimen repeated
every 5 weeks. The response rates were statistically significantly
different for the two arms (ie, 7% in the bolus arm vs 30% in the
infusional arm; P = .001). Although median survival was comparable in
the two arms, an analysis of proportion of patients surviving at 3
years showed a statistically significant benefit for the infusional arm.[18]

In the two subsequent MAOP studies, protracted infusional 5-FU was
used as a control arm and the experimental arm attempted to
modulate infusional 5-FU. In one study, weekly cisplatin
was added to infusional 5-FU. Although the addition of cisplatin did
not improve response rates or survival, the results confirmed the
response rate and survival pattern seen in the study comparing bolus
vs infusional single-agent 5-FU.[19] Similarly, the addition of
weekly N-(phosphonacetyl)-L-aspartate (PALA) to infusional 5-FU did
not increase response rate or median survival but again confirmed the
consistent response rate and survival pattern for infusional 5-FU
that was established in the first MAOP study.(personal communication,
J. Ahlgren, MD, June, 1997)

In 1996, Hanson et al reported on an Eastern Cooperative Oncology
Group (ECOG) four-arm study of 450 patients, comparing infusional
5-FU vs bolus 5-FU with or without weekly platinum. This is the only
study to replicate the MAOP use of protracted infusional 5-FU at a
similar dose rate. Response rates were 17% and 27%, respectively, for
the bolus and infusional arms; median survivals were comparable, and
platinum did not enhance therapeutic efficacy when used with either
5-FU delivery schedule.[13]

The study by Rougier et al, involving 155 patients, has only been
reported in abstract form.[14] In this study, the infusion duration
was 7 days repeated at 3-week intervals. The relative dose intensity
for this dose and cycle duration is 250 mg/m²/day. Results
showed that response rates doubled from 8% with the bolus schedule to
19% with infusional 5-FU (P = .02), and freedom from progression at 1
year increased from 15% to 26%, respectively (P = .04).

Finally, Weinerman et al published the National Cancer Institute of
Canada data comparing bolus and infusional 5-FU in 1992.[15] The
infusion duration (14 days repeated at 4-week intervals) was
intermediate between those of MAOP, ECOG, and Rougier et al, and the
dose intensity (176 mg/m2/week) was the lowest used in these
comparative trials. The response rate in the infusion arm was double
that in the bolus arm (6% vs 12%). No difference in survival was
observed, though progression-free survival was significantly longer
(P = .01) in the infusion arm.

Meta-Analysis of Bolus vs Infusional 5-FU

In 1998, a meta-analysis of all randomized trials comparing
infusional and bolus administration of 5-FU was published.[20] The
meta-analysis included the report by Leichman et al from the
Southwest Oncology Group (SWOG) and a study by Issacson et al.[21,22]
However, the SWOG study, which was actually a randomized phase II
trial that involved seven different arms to assess modulation of
various 5-FU administration schedules, was intended to identify
activity and not to draw comparative conclusions. The study from
Issacson et al is also problematic in that patients in both arms
received folinic acid in addition to either bolus or infusional 5-FU.
Lokich has stressed that modulation of 5-FU, when administered as an
infusion, necessitates a reduction in the dose rate of infusion and
increases the toxicity profile.[23] These concerns notwithstanding,
the meta-analysis was carried out with a database of 1,219 patients.
Tumor response was significantly higher in the continuous-infusion
arm (22% vs 14%; P = .002). Furthermore, although median survival
times were close, overall survival was significantly higher for
patients on infusional 5-FU (hazard ratio = 0.88; P = .04).

Infusion Duration vs Dose

The concept of dose intensity, popularized by Hryniuk in breast
cancer and in the use of 5-FU for colon cancer, suggests that a
critical determinant of response is the dose delivered over unit
time.[24] The original reviews were based on studies in which 48-hour
infusions of 5-FU were administered either weekly or at 2- or 3-week
intervals. In a review by Lokich and Anderson, the more protracted
infusions for 5, 7, 14 days or 10 weeks were compared (Table
2).[25] Response rates for each of these regimens differed
according to the duration of exposure; however, the dose intensity
(DI) for the various regimens was substantially different. For
example, for the 5-day infusion, the maximum tolerated dose was the
equivalent of 35.7 mg/m²/day administered over 4 weeks. In
comparison, the DI of the 4-week protracted infusion, for example,
was almost ten times that at 300 mg/m²/day. In fact, the
response rate was also ten times higher with the protracted infusion
and higher daily dose intensity regimen (3% vs 30%). For intermediate
treatment durations and dose intensities, the response rates were
similarly intermediate.

It is therefore unclear whether dose intensity and duration of
exposure are independent variables, although comparable response
rates have been reported for the protracted 5-FU infusion when
administered at 175 or 200 mg/m²/day, suggesting that infusion
duration may be more important than dose intensity.[26]

Oral Fluorinated Pyrimidines

The oral fluorinated pyrimidines are compounds that may emulate the
effects of parenteral continuous-infusion 5-FU. Phase III comparative
trials of such agents vs bolus 5-FU/leucovorin are under way in
patients with advanced colon cancer. Three of these agents are listed in
Table 3, two of whichcapecitabine (Xeloda) and UFT (tegafur
plus uracil)contain 5-FU as a prodrug. All of these drugs are
administered on an intermittent schedule using an arbitrary 7-day
rest period. These three agents and two additional fluorinated
pyrimidines have been reviewed by Pazdur[27] and by Punt.[28] These
agents emulate continuous-infusion 5-FU clinically in terms of
response rates (25% to 30%) and the observation of hand-foot
syndrome. However, there are some differences in the toxicity profile
of the oral fluorinated pyrimidines vs parenteral infusional 5-FU.
For example, diarrhea and hematologic consequences occur infrequently
with low-dose protracted parenteral infusion 5-FU. For some of the
oral fluorinated pyrimidines, however, diarrhea is a substantial
problem and represents the most common grade 3 or 4 toxicity.

Summary

Infusional delivery of 5-FU for 24 hours per day over extended
periods is superior to bolus administration of unmodulated 5-FU.
Results of a meta-analysis of six phase III clinical trials carried
out in the 1980s has confirmed the superior response rate and
improved survival in patients receiving 5-FU by infusion. No
advantage can be demonstrated for the biochemical modulation of
infusional administration of 5-FU.

The new oral fluorinated pyrimidine compounds represent an important
turning point in maximizing the effect of 5-FU and potentially
eliminating the need for parenteral access and ambulatory infusion pumps.

22. Issacson S: 5-Fluorouracil and folinic acid in the treatment of
colorectal carcinoma: A randomized trial of two different schedules
of administration. Second International Conference on
Gastro-Intestinal Cancer, Jerusalem, Israel, 1989.